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Prof A Malliri,
Dr K Simpson,
Prof Caroline Dive
Applications accepted all year round
Self-Funded PhD Students Only
About the Project
Small cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis. Underlying this aggressiveness is intra-tumoural heterogeneity driven by phenotypic plasticity wherein tumour cells transition from a neuroendocrine (NE) to a non-neuroendocrine (non-NE) phenotype. The presence of both NE and non-NE cells has been shown in mouse models to be required for metastasis and contributes also to therapeutic resistance. Therefore, understanding the mechanisms responsible for this transition from an NE to non-NE state is essential for understanding the aggressive nature of this disease.
We have been utilising patient circulating tumour cell-derived explant models which spontaneously undergo NE to non-NE transition. This valuable tool has allowed us to probe the intracellular signalling events behind this transition. Initial data from these models indicates that activation of the small GTPase RAC1 drives the loss of NE characteristics, including the downregulation of NE transcription factors and leads to the acquisition of a non-NE-like morphology, indicative of the initial steps of the NE to non-NE transition.
This research proposal centres on evaluating the role of RAC1 in this transition. The project’s first aim is to identify the transition-specific activators of RAC1 which we hypothesise could be therapeutic targets for inhibiting the transition. The second aim is to employ transcriptomic and proteomic approaches to determine the mechanisms downstream of RAC1 contributing to this transition. As such, this project will combine the expertise of the supervisory team in RAC1 signalling and SCLC biology with access to unique SCLC patient-derived models, presenting an unparalleled opportunity to uncover the mechanisms underpinning this essential process of SCLC progression.
The supervisory environment is welcoming and supportive and values inclusivity and diversity. The student will present their work internally and at major scientific conferences and receive mentoring for successful career progression alongside valuable training in transferable skills.
Training/techniques to be provided
The student will be trained to culture cells in both 2D and 3D and to visualise cells with various microscopes (including widefield and confocal) and approaches (epifluorescence, fluorescent biosensors and immunofluorescence); to perform techniques such as molecular cloning, viral transduction and plasmid and siRNA transfection, RNA and protein extraction, immunoprecipitation, immunoblotting, and qPCR; to undertake transcriptome and proteome analyses.
Entry Requirements
Candidates should hold (or be about to obtain) a minimum upper-second-class honours degree (or equivalent) in a relevant subject (such as biochemistry, molecular or cellular biology).
Preferably the candidate would also have (or be about to obtain) a master’s degree or have other extensive experience in research (such as through an industrial placement or working as a research assistant). Candidates with an interest in cancer cell biology are especially encouraged to apply.
How to Apply
For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the PhD Cancer Sciences.
For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit https://www.bmh.manchester.ac.uk/study/research/international/
Equality, Diversity & Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website
https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/
Funding Notes
Applications are invited from self-funded students. This project has a Band 3 fee.
Details of our different fee bands can be found on our website View Website
Details of our different fee bands can be found on our website View Website
References
1. Ginn L, Maltas J, Baker MJ, Chaturvedi A, Wilson L, Guilbert R, Amaral FMR, Priest L, Mole H, Blackhall F, Diamantopoulou Z, Somervaille TCP, Hurlstone A, Malliri A. A TIAM1-TRIM28 complex mediates epigenetic silencing of protocadherins to promote migration of lung cancer cells. PNAS, 120(40):e2300489120, 2023.
2. Pearsall SM, Williamson SC, Humphrey S, Hughes E, Morgan D, García Marqués FJ, Awanis G, Carroll R, Burks L, Shue YT, Bermudez A, Frese KK, Galvin M, Carter M, Priest L, Kerr A, Zhou C, Oliver TG, Humphries JD, Humphries MJ, Blackhall F, Cannell IG, Pitteri SJ, Hannon GJ, Sage J, Dive C, Simpson KL. Lineage Plasticity in SCLC Generates Non-Neuroendocrine Cells Primed for Vasculogenic Mimicry. J Thorac Oncol. 18(10):1362-1385, 2023.
3. Shue YT, Drainas AP, Li NY, Pearsall SM, Morgan D, Sinnott-Armstrong N, Hipkins SQ, Coles GL, Lim JS, Oro AE, Simpson KL, Dive C, Sage J. A conserved YAP/Notch/REST network controls the neuroendocrine cell fate in the lungs. Nature Communications 13(1):2690, 2022.
4. Payapilly A, Guilbert R, Descamps T, White G, Magee P, Zhou C, Kerr A, Simpson KL, Blackhall F, Dive C, Malliri A. TIAM1-RAC1 promote small-cell lung cancer cell survival through antagonizing Nur77-induced BCL2 conformational change. Cell Reports 37(6):109979, 2021.
5. Simpson KL, Stoney R, Frese KK, Simms N, Rowe W, Pearce SP, Humphrey S, Booth L, Morgan D, Dynowski M, Trapani F, Catozzi A, Revill M, Helps T, Galvin M, Girard L, Nonaka D, Carter L, Krebs MG, Cook N, Carter M, Priest L, Kerr A, Gazdar AF, Blackhall F, Dive C. A biobank of small cell lung cancer CDX models elucidates inter- and intratumoral phenotypic heterogeneity. Nature Cancer. 1(4):437-451, 2020.
2. Pearsall SM, Williamson SC, Humphrey S, Hughes E, Morgan D, García Marqués FJ, Awanis G, Carroll R, Burks L, Shue YT, Bermudez A, Frese KK, Galvin M, Carter M, Priest L, Kerr A, Zhou C, Oliver TG, Humphries JD, Humphries MJ, Blackhall F, Cannell IG, Pitteri SJ, Hannon GJ, Sage J, Dive C, Simpson KL. Lineage Plasticity in SCLC Generates Non-Neuroendocrine Cells Primed for Vasculogenic Mimicry. J Thorac Oncol. 18(10):1362-1385, 2023.
3. Shue YT, Drainas AP, Li NY, Pearsall SM, Morgan D, Sinnott-Armstrong N, Hipkins SQ, Coles GL, Lim JS, Oro AE, Simpson KL, Dive C, Sage J. A conserved YAP/Notch/REST network controls the neuroendocrine cell fate in the lungs. Nature Communications 13(1):2690, 2022.
4. Payapilly A, Guilbert R, Descamps T, White G, Magee P, Zhou C, Kerr A, Simpson KL, Blackhall F, Dive C, Malliri A. TIAM1-RAC1 promote small-cell lung cancer cell survival through antagonizing Nur77-induced BCL2 conformational change. Cell Reports 37(6):109979, 2021.
5. Simpson KL, Stoney R, Frese KK, Simms N, Rowe W, Pearce SP, Humphrey S, Booth L, Morgan D, Dynowski M, Trapani F, Catozzi A, Revill M, Helps T, Galvin M, Girard L, Nonaka D, Carter L, Krebs MG, Cook N, Carter M, Priest L, Kerr A, Gazdar AF, Blackhall F, Dive C. A biobank of small cell lung cancer CDX models elucidates inter- and intratumoral phenotypic heterogeneity. Nature Cancer. 1(4):437-451, 2020.
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